Tetrahydroisoquinoline derivatives

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  and R 2  are each independently --H or lower alkoxy; 
     R 3  and R 4  are each independently lower alkyl; and 
     R 5  and R 6  are each --OCH 3 , or together form --OCH 2  O-- or --OCH 2  CH 2  O-- 
     and pharmaceutically acceptable acid addition salts thereof are calcium channel blockers useful for treating cardiovascular disorders including angina, hypertension and congestive heart failure.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel3-(4-cyano-4-phenylalkyl)tetrahydroisoquinoline derivatives and thepharmaceutically acceptable salts thereof, pharmaceutical compositionscontaining said derivatives or salts, and the use thereof to treatcardiovascular disorders including angina, hypertension, and congestiveheart disease. This invention also relates to a novel process forpreparing the compounds of the invention, and novel intermediatestherefor.

2. Related Disclosure

Certain other calcium channel blocking agents are known, such asverapamil,N-[4-(3,4-dimethoxyphenyl)-4-cyano-4-(prop-2-yl)butyl]-N-(3,4-dimethoxyphenethyl)-N-methylamine,(U.S. Pat. No. 3,261,859). Although verapamil has enjoyed widespreadcommercial success, it is short-acting, necessitating administrationthree or four times per day. Also, it is cardiodepressive, and decreasescardiac conduction. It has now been found that the compounds of theinvention are less cardiodepressive and longer-acting than verapamil.Compounds of the invention are orally active and decrease afterload andpreload, while increasing coronary bloodflow. Compounds of the inventionalso increase the heart rate pressure product without increasing theheart rate. Compounds of the invention do not cause pathologicalprolongation of A-V conduction at effective concentrations, and do notcause orthostatic hypotension. Compounds of the invention decrease ECGST-segment elevation in pacing-induced angina models.

DEFINITIONS

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

The term "lower alkyl" refers to a straight or branched chain monovalentsubstituent consisting solely of carbon and hydrogen, containing nounsaturation and having from one to five carbon atoms. Examples of loweralkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, and 3-pentyl.

The term "lower alkoxy" refers to radicals of the form RO--, where R islower alkyl as defined above.

The term "alkanol" refers to lower alkyl alcohols such as methanol,ethanol, propanol, isopropanol, butanol, and the like.

The term "halo" as used herein refers to chloro, bromo and iodo.

The term "aryl" refers to aromatic radicals consisting entirely ofcarbon and hydrogen, containing from 6 to 12 carbon atoms. Examples ofaryl groups are phenyl, naphthyl, and the like.

The term "acylating agent" refers to compounds which are useful foradding a radical of the form RC(O)--(where R is lower alkyl) to ahydroxy group, e.g., for converting HO-- to CH₃ COO--. Acylating agentsinclude acylating agents such as acetic anhydride and acetyl chloride.Other acylating agents within the scope of this definition include acylanhydrides and acyl halides such as propanoyl chloride, butanoylbromide, 3-methylbutanoyl chloride and the like.

The term "acyl anhydride" refers to compounds of the formula R_(a)C(O)--O--C(O)R_(b), where R_(a) and R_(b) are each independently loweralkyl, which are typically produced by the condensation of two loweralkyl carboxylic acids. Exemplary acyl anhydrides are formic anhydride,acetic anhydride, formic-acetic anhydride, formic-pentanoic anhydride,and pentanoic-pentanoic anhydride.

The term "noble metal catalyst" refers to catalysts in which the activecomponent is primarily a noble metal, such as platinum, palladium,osmium, and the like. Such catalysts are commonly used in the practiceof catalytic hydrogenation, hydrogenolysis, and similar reactions.

The term "catalytic amount" refers to the amount of catalyst that mustbe added in order to effect catalysis, i.e., to increase the yield orrate of reaction by a significant amount. Due to the nature ofcatalysis, the "catalytic amount" will vary widely depending on thereaction and the catalyst used. However, given the particular catalystand reaction, one of ordinary skill in the art will be above todetermine the catalytic amount through routine experimentation.

The term "formaldehyde source" refers to formaldehyde and compoundswhich can be used to supply formaldehyde to a reaction mixture. Forexample, paraformaldehyde decomposes in solution to yield formaldehyde,and is thus a formaldehyde source within the meaning of this definition.Formalin also falls within the scope of this definition.

The term "paraformaldehyde" refers to polymerized formaldehyde, (CH₂O)_(n). Paraformaldehyde is commerically available, and is used as asource of formaldehyde in chemical reactions.

The term "boron-based reducing agent" refers to sodium borohydride,diborane, and similar alkylboron reducing agents.

The term "metallic base" refers to metal-based bases such as sodium,NaH, Raney nickel, potassium t-butoxide, lithium aluminum hydride,NaNH₂, and the like.

The term "protecting group" refers to a group that is used to preventhydroxy or carbonyl groups from reacting undesirably during thepreparation of compounds of the invention. Examples of protecting groupsare benzyl ethers, ketals (e.g., acetonides), and esters. Protectinggroups are ideally easily applied and removed under conditions unlikethe reaction conditions used in the preparations. For example, t-butylcarbonate esters are stable under the SN₂ reaction conditions used inpreparation of compounds of formula 1, but are easily displaced usingformic acid and formic-acetic anhydride.

The term "pharmaceutically acceptable salts" refers to salts of thesubject compounds which possess the desired pharmacological activity andwhich are neither biologically nor otherwise undesirable. These saltsare acid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid;or organic acids such as acetic acid, propionic acid, glycolic acid,pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid and the like.

The term "treatment" as used herein covers any treatment of a disease ina mammal, particularly a human, and includes:

(i) preventing the disease from occurring in a subject which may bepredisposed to the disease but has not yet been diagnosed as having it;

(ii) inhibiting the disease, i.e., arresting its development; or

(iii) relieving the disease, i.e., causing regression of the disease.

Compounds of formula 1 are named and numbered as derivatives ofisoquinoline using a modified form of IUPAC nomenclature. For example,the compound below is named3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline:##STR2##

Compounds of formula 1 have two asymmetric sites, C₃ and C₄, (markedabove as * and **, respectively), and thus can exist as diastereomers.Individual isomers of compounds of formula 1 are named herein using theIUPAC R-S convention, sometimes called the "sequence rule." Adescription of the R-S convention may be found, for example, in"Introduction to Organic Chemistry" by A. Streitwieser, Jr. and C.Heathcock, (Macmillan Pub. Co., New York, 1976), pages 110-114.Diastereomers will be indicated as (3R, 4'S), (3R, 4'R), (3S, 4'S) or(3S, 4'R) as appropriate. For example, the compound illustrated above is(3R, 4'S). Where appropriate, the optical activity of a compound may beindicated by (+), (-), or (±), referring to the direction in which asolution of the compound rotates a plane of polarized light.

SUMMARY OF THE INVENTION

One aspect of the invention is a compound of the formula ##STR3## or apharmaceutically acceptable acid addition salt thereof, wherein R₁ andR₂ are each independently --H or lower alkoxy, R₃ and R₄ are eachindependently lower alkyl, and R₅ and R₆ are each --OCH₃ or togetherform --OCH₂ O-- or --OCH₂ CH₂ O--.

Another aspect of the invention is a mixture of compounds of formula 1.

Another aspect of the invention is a pharmaceutical composition whichcomprises a compound of formula 1 and a pharmaceutically acceptableexcipient.

Another aspect of the invention is a method for treating cardiovasculardiseases susceptible to treatment by calcium channel blockade, whichdiseases include angina, hypertension, and congestive heart failure.

Another aspect of the invention is a novel process for preparingcompounds of formula 1.

Another aspect of the invention is an intermediate of formula 11 whichis useful for preparing compounds of formula 1: ##STR4## andpharmaceutically acceptable salts thereof, where R₁, R₂, R₄, R₅ and R₆are as defined above.

Another aspect of the invention is an intermediate of formula 8 which isuseful for preparing intermediates of formula 11: ##STR5## andpharmaceutically acceptable salts thereof, where R₁, R₂, R₄, R₅ and R₆are as defined above.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

One aspect of the invention is a compound of the formula ##STR6## or apharmaceutically acceptable acid addition salt thereof, wherein R₁ andR₂ are each independently --H or lower alkoxy; R₃ and R₄ are eachindependently lower alkyl; and R₅ and R₆ are each --OCH₃, or togetherform --OCH₂ O-- or --OCH₂ CH₂ O--. A preferred subgenus of the inventionis the compound wherein R₄ is isopropyl. A preferred class is thecompound wherein R₃ is methyl. A preferred subclass is the compoundwherein R₁ and R₂ are each H, particularly where R₅ and R₆ are each--OCH₃. A presently preferred embodiment is the compound (3S, 4'S)3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline.Another presently preferred embodiment is the compound (3S, 4'S)3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline.HCl.

Another aspect of the invention is a mixture of compounds of formula 1.A preferred class is an approximately racemic mixture of diastereomers.A presently preferred embodiment is the mixture of the (3S, 4'S), (3S,4'R), (3R, 4'S), and (3R, 4'R) isomers of3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline.Another presently preferred embodiment is the mixture of the (3S, 4'S),(3S, 4'R), (3R, 4'S), and (3R, 4'R) isomers of3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl.Another preferred embodiment is an approximately equimolar mixture of(3S, 4'S) and (3S, 4'S)3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline.

Another aspect of the invention is a pharmaceutical composition whichcomprises a compound of formula 1 and a pharmaceutically acceptableexcipient.

Another aspect of the invention is a method for treating cardiovasculardiseases susceptible to treatment with calcium channel blockers, whichdiseases include angina, hypertension, and congestive heart failure,which method comprises administering an effective amount of a compoundof formula 1 to a mammal in need thereof.

Another aspect of the invention is a process for preparing compounds offormula 1, which process comprises heating at 70° to 110° C. for 1 to 24hours a mixture of formic acid, a formaldehyde source, and a compound offormula 11: ##STR7## wherein R₁ and R₂ are each independently --H orlower alkoxy; R₄ is lower alkyl; and R₅ and R₆ are each --OCH₃, ortogether form --OCH₂ O-- or --OCH₂ CH₂ O--. A preferred subgenus of theinvention is the process wherein R₁ and R₂ are each --H, R₄ isprop-2-yl, and R₅ and R₆ are each --OCH₃. A preferred class is theprocess wherein said mixture is heated at about 80° C. for 2 to 8 hours.A preferred subclass is the process wherein said compound of formula 11is obtained by mixing in an inert solvent an acylating agent (preferablyacetic anhydride), a catalytic amount of base (preferably4-dimethylaminopyridine), and a compound of formula 8 ##STR8## whereinR₁ and R₂ are each independently --H or lower alkoxy; R₄ is lower alkyl;and R₅ and R₆ are each --OCH₃, or together form --OCH₂ O-- or --OCH₂ CH₂O--

to form a first resulting product; and then reacting a mixture of saidfirst resulting product, a first alkanol (preferably 2-propanol), aninert solvent (preferably CH₂ Cl₂), and a boron-based reducing agent(preferably NaBH₄) to produce a second resulting product; and heating amixture of said second resulting product (at 30°-60° C.), ammoniumformate, a noble metal catalyst (preferably 5% Pd/C), and a secondalkanol (preferably methanol). A preferred species is the processwherein said compound of formula 8 is obtained by heating (at 40°-65°C.) a mixture of a third lower alkanol (preferably 2-propanol), acatalytic amount of a fluoride salt (preferably KF), a compound offormula 4, and a compound of formula 7: ##STR9## wherein R₁ and R₂ areeach independently --H or lower alkoxy; R₄ is lower alkyl; and R₅ and R₆are each --OCH₃, or together form --OCH₂ O-- or --OCH₂ CH₂ O--.

ADMINISTRATION AND FORMULATION

Another aspect of the present invention relates to pharmaceuticalcompositions useful in the treatment of cardiovascular diseases such ashypertension, congestive heart failure, angina, migraine, andvasospastic disorders, particularly in the treatment of hypertension ina mammalian subject, comprising a therapeutically effective amount of acompound of formula 1, or a pharmaceutically acceptable acid additionsalt thereof, in admixture with a pharmaceutically acceptable non-toxiccarrier. A therapeutically effective amount is that amount which, whenadministered to a mammal in need thereof, is sufficient to effecttreatment, as defined above. Thus, the level of the drug in theformulation can vary from about 5 percent weight (%w) to about 95%w ofthe drug based on the total formulation and about 5%w to 95%w excipient.Preferably the drug is present at a level of about 10%w to about 70%w.

Useful pharmaceutical carriers for the preparation of the pharmaceuticalcompositions hereof can be solids or liquids. Thus, the compositions cantake the form of tablets, pills, capsules, powders, sustained releaseformulations, solutions, suspensions, elixirs, aerosols, and the like.Carriers can be selected from the various oils, including those ofpetroleum, animal, vegetable or synthetic origin, for example, peanutoil, soybean oil, mineral oil, sesame oil, and the like. Water, saline,aqueous dextrose, and glycols are preferred liquid carriers,particularly for injectable solutions. Suitable pharmaceuticalexcipients include starch, cellulose, talc, glucose, lactose, sucrose,gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate,sodium stearate, glycerol monostearate, sodium chloride, dried skimmilk, glycerol, propylene glycol, water, ethanol, and the like. Othersuitable pharmaceutical carriers and their formulations are described in"Remington's Pharmaceutical Sciences" by E. W. Martin.

Another aspect of the present invention relates to a method for treatingcardiovascular diseases such as hypertension, congestive heart failure,angina, and vasospastic disorders in a mammalian subject (particularly ahuman) which method comprises administering a therapeutically effectiveamount of a compound of formula 1, or a pharmaceutically acceptable acidaddition salt thereof, to a mammal in need thereof, especially a human.

In the practice of the above described method of the present invention atherapeutically effective amount of the compound of formula 1 or apharmaceutical composition containing same is administered via any ofthe usual and acceptable methods known in the art, either singly or incombination with another compound or compounds of the present inventionor other pharmaceutical agents. These compounds or compositions can thusbe administered orally, systemically (e.g., transdermally, intranasallyor by suppository) or parenterally (e.g., intramuscularly,subcutaneously and intravenously), and can be administered either in theform of solid or liquid dosages including tablets, solutions,suspensions, aerosols, and the like, as discussed in more detail above.It is preferred to administer compounds of formula 1 orally.

The formulation can be administered in a single unit dosage form forcontinuous treatment or in a single unit dosage form ad libitum whenrelief of symptoms is specifically required.

The Spontaneously Hypertensive Rat (SHR) assay is an accepted test fordetermining antihypertensive activity. See, e.g., J. Roba, et al., Arch.Int. Pharmacodyn., 200, 182 (1972). The compounds of the inventionexhibit antihypertensive activity in the SHR assay.

Other accepted tests for cardiovascular activity include rat aorticstrip assays, ultrasonic two-dimensional echocardiography andanesthetized dog assays. See, e.g., P. Gueret, M.D., et al.,Circulation, 62(6), 1308 (1980), and M Tripp. American J. of Physiology,232(2), H173 (1977). The compounds of the invention demonstrate positiveactivity in these assays, also.

In view of the foregoing as well as in consideration of the degree ofseverity of the condition being treated, age of subject and so forth,all of which factors are routinely determinable by one skilled in theart, the effective dosage in accordance herewith can vary over a widerange. Generally, a therapeutically effective amount ranges from about0.7 to about 7 mg/kg body weight per day and preferably, for example,for antihypertensive use, from about 0.8 to about 1.5 mg/kg body weightper day. In alternative terms, for an average 70 kg adult human subject,a therapeutically effective amount in accordance herewith would be, inpreferred embodiments from about 50 mg to about 500 mg per day persubject, and preferably from about 60 mg to 100 mg per day per subject.

PREPARATION OF THE INVENTION

Compounds of the invention may be preferred by the methods illustratedin Schemes I, II, or III. Scheme I illustrates the presently preferredmethod of preparing compounds of formula 1. Scheme II illustrates amethod for preparing optically pure diastereomers from commerciallyavailable starting materials. Scheme III illustrates an alternate methodfor preparing compounds of the invention. ##STR10##

In the Schemes above, Ac refers to acetyl (CH₃ CO--), LDA refers tolithium diisopropylamide, DMAP refers to 4-dimethylaminopyridine, Xrefers to halo, Ts refers to tosyl (p-toluenesulfonyl), DAB refers todisiamylborane, Ms refers to mesyl (methylsulfonyl), Me refers to methyl(CH₃ --), Et refers to ethyl, i-Pr refers to isopropyl, t-Bu refers totert-butyl, and φ refers to phenyl. Each R is independently lower alkyl,and R₁, R₂, R₃, R₄, R₅, and R₆ have the meanings described in thebroadest description of the invention.

According to Scheme I, an optionally substituted dimethoxybenzaldehydeof formula 2, nitromethane and a catalytic amount of ammonium acetate(about 10 mol% per dimethoxybenzaldehyde) are heated to about 70°-100°C. for about 2-6 hours. The resulting product is precipitated from amixture of water and isopropanol (about 7:1) to yield a nitrostyrenederivative of formula 3 (step 1). For example, 3,4-dimethoxybenzaldehydeis treated with NH₄ OAc and nitromethane to yield3,4-dimethoxy-β-nitrostyrene (3). Alternatively, one can purchase3,4-dimethoxy-β-nitrostyrene commercially.

The nitrostyrene derivative (3) is then cooled to about -10°-10° C.,treated with silica gel, and reduced using 1.5-4 equivalents of aboron-based reducing agent, e.g., sodium borohydride, with 2-propanoland an inert solvent, e.g., CH₂ Cl₂, at -10°-10° C. for 20-60 minutes toproduce a nitrophenylethane derivative of formula 4 (step 2). Forexample, 3,4-dimethoxy-β-nitrostyrene (3) is treated with 2-propanol andSiO₂ in CH₂ Cl₂ at 0°-10° C. for 20 minutes, followed by reduction with1.5 eq NaBH₄ at 5° C. for 30 minutes to yield2-(3,4-dimethoxyphenyl)nitroethane (4).

An optionally substituted phenylacetonitrile is then alkylated with anω-halopropionaldehyde acetal using a strong metallic base, in a polar,aprotic solvent. The desired phenylacetonitrile derivative is firstdeprotonated by adding about 1 eq of a strong metallic base, e.g., NaH,in a polar aprotic solvent at 15°-21° C. over 25-50 minutes. Theresulting mixture is then stirred for 1-3 hours, and about 1 eq of3-chloropropionaldehyde diethylacetal is added to yield a derivative offormula 5 (step 3). For example, 2-(3,4-dimethoxyphenyl)-acetonitrile indimethyl formamide (DMF) is added to NaH at 18°-20° C. over a 30 minuteperiod, stirred for one hour, and then treated with3-chloropropionaldehyde diethylacetal in DMF to yield2-(3,3-diethoxypropyl)-2-(3,4-dimethoxyphenyl)acetonitrile (5).

The resulting acetal derivative of formula 5 is then alkylated withabout 1 eq of an alkylhalide using a strong metallic base and acatalytic amount of an iodide source, e.g., 2-iodopropane or NaI, in apolar aprotic solvent at about 10°-40° C. for 2-18 hours, followed bytreatment with sufficient ice water to decompose excess base, to yield adialkylated derivative of formula 6. For example,2-(3,3-diethoxypropyl)-2-(3,4-dimethoxyphenyl)acetonitrile (5) in DMF istreated with a slight molar excess of 2-chloropropane (and 0.1-5 mol%2-iodopropane) at 20° C., stirred for 10 minutes, then treated with 1 eqNaH in mineral oil and slowly heated to 40° C. After adding 200 mL icewater and purifying the product,2-(3,3-diethoxypropyl)-2-(prop-2-yl)-2-(3,4-dimethoxyphenyl)acetonitrile(6) is obtained.

The resulting acetal intermediate of formula 6 is then hydrolyzed usinga concentrated protic acid and a polar solvent at 30°-60° C. for 5-60minutes (step 5). For example,2-(3,3-diethoxypropyl)-2-(prop-2-yl)-3,4-dimethoxyphenyl)acetonitrile(6) is heated at 55° C. in THF/water (3:1) with concentrated HCl for 15minutes to yield 1-(i-propyl)-1-(3,4-dimethoxyphenyl)-1-cyanobutanal(7).

The resulting intermediate of formula 7 is then condensed with theintermediate of formula 4 in the presence of a catalytic amount (about0.1-5 mol%) of a fluoride salt, e.g., KF, and a base in an alcoholsolvent at 40°-65° C. for 12-60 hours to produce a diaryl nitrohexanolof formula 8 (step 6). For example,1-(prop-2-yl)-1-(3,4-dimethoxyphenyl)-1-cyanobutanal (7) is reacted with2-(3,4-dimethoxyphenyl)nitroethane (4) in 2-propanol with a catalyticamount of KF to yield1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol(8).

The resulting nitrohexanol intermediate of formula 8 is then acylatedwith an acylating agent, (for example acetic anhydride and a catalyticamount of dimethylaminopyridine (DMAP), or acetyl chloride) in an inert,aprotic, polar solvent for 20-120 minutes to produce a nitrohexanolacylate of formula 9 (step 7). For example,1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol(8) is mixed with Ac₂ O and DMAP in CH₂ Cl₂ for 40 minutes to yieldO-acetyl-1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol(9).

The resulting nitrohexanol acetate of formula 9 is then reduced using aboron-based reducing agent, e.g., sodium borohydride, in a 2° or 3°alkanol at 25°-80° C. for 3-15 hours to produce a nitrohexane derivativeof formula 10 (step 8). For example,O-acetyl-1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol(9) is heated with NaBH₄ in 2-propanol at reflux for 3-15 hours to yield1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane(10).

The intermediate of formula 10 is then reduced to an amine of formula11, e.g., by treatment with ammonium formate in alcohol using a Pd/Ccatalyst at 30°-60° C. for 30 minutes to 48 hours (step 9). For example,1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane(10) is heated at reflux with HCO₂ NH₄ in methanol over 5% Pd/C forabout 24 hours to produce1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(11).

The intermediate of formula 11 is then cyclized and the amine methylatedby reaction with a formaldehyde source, (e.g., formaldehyde, formalin,paraformaldehyde or the like) and formic acid at 70°-110° C. for 1-24hours to yield a tetrahydroisoquinoline of formula 1 (step 10). Forexample,1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane(11) is heated at 80°-100° C. with paraformaldehyde and formic acid for2-8 hours to yield3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline(1) as a racemic mixture.

The free base of formula 1 may be converted to a pharmaceuticallyacceptable salt, if desired, by dissolving the base in a suitablesolvent, such as an alcohol, and treating with the appropriate acid. Forexample,3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline(1) is dissolved in isopropanol, and HCl gas is bubbled through thesolution. The solution is then saturated with ether to precipitate3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl.

In summary, compounds of formula 1 may be prepared via Scheme I byheating at 70°-110° C. for 1-24 hours a mixture of a compound of formula11, a formaldehyde source, and formic acid.

Specific optical isomers may be prepared by the method illustrated inScheme II. L-3,4-dimethoxyphenylalaninol (12) or another suitablephenylaminopropanol derivative is prepared as described by A. W.Schrecker and J. L. Hartwell, J. Am. Chem. Soc., 79, 3827 (1957). Theamino group is then protected by reaction with di-t-butyldicarbonate toyield a carbamate derivative of formula 13 (step 1). For example,L-3,4-dimethoxyphenylalaninol (12) is heated at reflux intetrahydrofuran (THF) for one hour with di-t-butyldicarbonate to yield3-(3,4-dimethoxyphenyl)-L-2-(t-butoxycarbonylamino)propan-1-ol (13).

The hydroxy group is then converted to a suitable leaving group, e.g.,by conversion to a tosylate (step 2). For example,3-(3,4-dimethoxyphenyl)-L-2-(t-butoxycarbonylamino)propan-1-ol (13) isstirred at room temperature for 2 days with p-toluenesulfonyl chlorideand a catalytic amount of DMAP in pyridine to yield3-(3,4-dimethoxyphenyl)-L-2-(t-butoxycarbonylamino)-1-tosyloxypropane(14).

The tosylate of formula 14 is then treated with vinyl magnesium bromideand CuI in an inert solvent to produce the corresponding pent-1-enederivative of formula 15 (step 3). For example,3-(3,4-dimethoxyphenyl)-L-2-(t-butoxycarbonylamino)-1-tosyloxypropane(14) is treated with vinyl magnesium bromide and CuI in THF at -70° C.for 1/2 hour and allowed to warm to 0° C. to yield5-(3,4-dimethoxyphenyl)-L-4-(t-butoxycarbonylamino)pent-1-ene (15).

The resulting pentene derivative is then converted to a pentanolderivative, e.g., by reaction with DAB in a suitable inert solvent (step4). For example,5-(3,4-dimethoxyphenyl)-L-4-(t-butoxycarbonylamino)-pent-1-ene (15) isadded to DAB in THF at 0° C., stirred at room temperature for 1/2 hour,and treated with NaOH and H₂ O₂ at room temperature for 1/2 hour toyield 5-(3,4-dimethoxyphenyl)-L-4-(t-butoxycarbonylamino)-pentan-1-ol(16).

The pentanol derivative is then converted to a pentyl iodide derivativeof formula 17, e.g., by converting the pentanol derivative to amesylate, followed by treatment of the mesylate with sodium iodide (step5). For example,5-(3,4-dimethoxyphenyl)-L-4-(t-butoxycarbonylamino)pentan-1-ol (16) istreated with NEt₃ and methanesulfonyl chloride in CH₂ Cl₂ at 0° C. for10 min. The product is separated, dissolved in acetone, and heated atreflux for 1/2 hour with NaI to yield5-(3,4-dimethoxyphenyl)-L-4-(t-butoxycarbonylamino)-1-iodopentane (17).

An appropriate compound of formula 6 (see Scheme I) is treated with astrong base, e.g., LDA, in an inert solvent and is then reacted with theiodopentane derivative of formula 17 to form the aminohexane derivativeof formula 18 (step 6). For example,(±)-2-(i-propyl)-2-(3,4-dimethoxyphenyl)acetonitrile (6) is deprotonatedwith LDA in THF at -70° C., then reacted with5-(3,4-dimethoxyphenyl)-L-4-(t-butoxycarbonylamino)-1-iodopentane (17)to yield1-(3,4-dimethoxyphenyl)-L-(2-t-butoxycarbonylamino)-(±)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(18).

The resulting protected aminohexane derivative is then converted to aformylamino hexane derivative of formula 19 (step 7). For example,1-(3,4-dimethoxyphenyl)-L-(2-t-butoxycarbonylamino)-(±)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(18) is treated first with formic acid, then with formic-aceticanhydride to produce1-(3,4-dimethoxyphenyl)-L-2-(formylamino)-(±)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(19). The (+) and (-) isomers may then be separated by medium pressurechromatography using ethyl acetate as the solvent. The (-) isomer,1-(3,4-dimethoxyphenyl)-L-2-(formylamino)-(-)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(19A), elutes first, followed by1-(3,4-dimethoxyphenyl)-L-2-(formylamino)-(+)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(19B).

The formylaminohexane derivative is then cyclized to atetrahydroisoquinoline of formula 20, e.g., by treatment withphosphorous oxychloride followed by NaBH₄ (step 8). For example,1-(3,4-dimethoxyphenyl)-L-2-(formylamino)-(-)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(19A) is treated with POCl₃ in CH₃ CN, followed by reaction with NaBH₄in ethanol to produceL-(-)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(20A).

The resulting isoquinoline derivative of formula 20 is then N-alkylated,e.g., using paraformaldehyde in formic acid to produce a compound offormula 1. For example,L-(-)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(20A) is reacted with paraformaldehyde in formic acid to produceL-(-)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline(1). Alternatively, one can alkylate an intermediate of formula 19 usinga strong base and an alkylating agent of the form R₃ -L, where L is anappropriate leaving group, such as tosyl. For example,L-(-)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(20A) is reacted with LDA and propyltosylate to produceL-(-)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-propyl-1,2,3,4-tetrahydroisoquinoline(1).

Alternatively, one may prepare compounds of the invention via theprocedures of Scheme III. In the first step, a derivative of formula 6a(see Scheme II) is alkylated with a 1,3-dihalopropane using a strongbase in a suitable aprotic solvent to produce a derivative of formula 21(step 1). For example, 2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrileis treated with sodium amide in toluene and 1-bromo-3-chloropropane toproduce2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-chloropropyl)-acetonitrile(21).

The chloro derivative of formula 21 is then converted to an iodidederivative of formula 22 by treatment with an appropriate salt (step 2).For example,2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-chloropropyl)acetonitrile (21)is treated with NaI in acetone at reflux to yield2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22).

The iodo derivative of formula 22 is then reacted with a3-(3,4-dimethoxyphenyl)propionic acid derivative (optionally substitutedat phenyl positions 2 and/or 5) in the presence of a strong base toproduce a derivative of formula 23 (step 3). For example,2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) isreacted with lithium diisopropylamide, hexamethylphosphoramide, and3-(3,4-dimethoxyphenyl)propionic acid in THF to yield1-(3,4-dimethoxyphenyl)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-2-oicacid (23).

The derivative of formula 23 is then converted to a formamide derivativeof formula 19, e.g., by treating with diphenylphosphoryl azide and base,followed by treatment with sodium borohydride. For example,1-(3,4-dimethoxyphenyl)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-2-oicacid (23) is treated with triethylamine and diphenylphosphoryl azide inTHF, then reacted with NaBH₄ in dimethoxyethane to yield1-(3,4-dimethoxyphenyl)-2-(formylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(19). The intermediates of formula 19 may be separated intodiastereomeric pairs of silica gel chromatography using ethylacetate-hexane (4:1) as an eluent. The intermediates of formula 19 maybe converted to compounds of formula 1 by the procedures of Scheme II,steps 8-9.

The free base of formula 1 may be converted to a pharmaceuticallyacceptable salt, if desired, by dissolving the base in a suitablesolvent, such as an alcohol, and treating with the appropriate acid. Forexample,L-(-)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline(1) is dissolved in isopropanol, and HCl gas is bubbled through thesolution. The solution is then saturated with ether to precipitateL-(-)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl.

The following Preparations and Examples are intended as furtherillustrations of the invention, and are not intended as limitations onthe scope thereof.

PREPARATION 1 (Intermediates of Formula 3)

(A) A mixture of 3,4-dimethoxybenzaldehyde (2, 100 g, 0.60 mol,obtainable through Aldrich Chemical Co.), ammonium acetate (10 g,Aldrich), and nitromethane (800 mL) was heated over a steam bath for 2.5hours. The mixture was then cooled to room temperature, mixed withisopropanol (500 mL), and slowly added to water (3.5 L) to precipitatethe product, 3,4-dimethoxy-β-nitrostyrene (3, 114 g, m.p. 142°-143° C.).

(B) Similarly, proceeding as in part (A) above but substituting3,4,5-trimethoxybenzaldehyde, 2,3,4-trimethoxybenzaldehyde,2,3,4,5-tetramethoxybenzaldehyde,3,4-dimethoxy-2,5-diethoxybenzaldehyde, or3,4-dimethoxy-2,5-dipentoxybenzaldehyde for 3,4-dimethoxybenzaldehyde,the following compounds are prepared:

3,4,5-trimethoxyphenyl-β-nitrostyrene;

2,3,4-trimethoxyphenyl-β-nitrostyrene;

2,3,4,5-tetramethoxyphenyl-β-nitrostyrene;

3,4-dimethoxy-2,5-diethoxyphenyl-β-nitrostyrene; and

3,4-dimethoxy-2,5-dipentoxyphenyl-β-nitrostyrene.

PREPARATION 2 (Intermediates of Formula 4)

(A) A mixture of 3,4-dimethoxy-β-nitrostyrene (3, 140 g, 0.67 mol) 3°C.), methylene chloride (3.2 L), and isopropanol (2.0 L) was cooled to5° C. and treated with silica gel (1.32 Kg, 70-230 mesh, EM Reagents).After stirring at 5° C. for 20 minutes, NaBH₄ (88.6 g, 2.34 mol, AlfaChemicals) was added over 30 minutes, followed by another 30 minutes ofstirring at 5° C. The reaction was then quenched by adding 10% aqueousHCl (280 mL). The silica gel was filtered off and washed with CH₂ Cl₂(2×150 mL). The combined filtrates were washed with water (1.0 L)followed by brine (1.0 L). The organic layer was removed in vacuo toyield 2-(3,4-dimethoxyphenyl)-1-nitroethane (4, 132 g, m.p. 50°-52° C.)as a pale yellow oil which solidified on standing.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 1(B) for 3,4-dimethoxy-β-nitrostyrene,the following compounds are prepared:

2-(3,4,5-trimethoxyphenyl)-1-nitroethane;

2-(2,3,4-trimethoxyphenyl)-1-nitroethane;

2-(2,3,4,5-tetramethoxyphenyl)-1-nitroethane;

2-(3,4-dimethoxy-2,5-diethoxyphenyl)-1-nitroethane; and

2-(3,4-dimethoxy-2,5-dipentoxyphenyl)-1-nitroethane.

PREPARATION 3 (Intermediates of Formula 5)

(A) A mixture of 2-(3,4-dimethoxyphenyl)acetonitrile (5, 55 g, 0.31 mol,Aldrich) in dimethylformamide (DMF, 200 mL) in an addition funnel wasadded to a mixture of NaH (50% NaH in mineral oil, 15.84 g, 0.33 mol) inDMF (50 mL) over 30 minutes at 18°-20° C. After stirring for one hour, asolution of 3-chloropropanal diethylacetal (53 mL, 0.316 mol, Aldrich)in DMF (50 mL) was added and stirred for about 3 hours to produce2-(3,4-dimethoxyphenyl)-2-(3,3-diethoxypropyl)acetonitrile (5) which wasused in the next step without further treatment.

(B) Similarly, proceeding as in part (A) above but substituting2-nitriloethylbenzo-1,4-dioxan or 2-nitriloethylbenzo-1,3-dioxole for2-(3,4-dimethoxyphenyl)acetonitrile, the following compounds areprepared:

2-(1,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-acetonitrile; and

2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-acetonitrile.

PREPARATION 4 (Intermediates of Formula 6)

(A) To the product mixture resulting from Preparation 3(A) above wasadded in one portion a solution of 2-chloropropane (39.5 mL, 0.43 mol)and 2-iodopropane (0.04 mL) in DMF (50 mL). After stirring for 10minutes, a mixture of NaH in mineral oil (50%, 15.9 g, 0.33 mol) wasadded, and the resulting mixture heated to 40° C. and stirred for 18hours. The mixture was then cooled to room temperature, and ice water(200 mL) added. The mixture was extracted with hexane (500 mL) to removethe mineral oil, which was then discarded. The aqueous DMF layer wasdiluted with water (800 mL) and extracted with ethyl acetate (3×500 mL).The ethyl acetate extract was evaporated to yield2-(3,4-dimethoxyphenyl)-2-(3,3-diethoxypropyl)-2-isopropylacetonitrileas an oil (97.6 g, b.p. 164°-166° C./0.2 mmHg, MS m/e 349(M+)).

(B) Similarly, proceeding as in part (A) above but substitutingmethylchloride, chloroethane, 2-chlorobutane, or 3-bromopentane for2-chloropropane, the following compounds are prepared:

2-(3,4-dimethoxyphenyl)-2-(3,3-diethoxypropyl)-2-methylacetonitrile;

2-(3,4-dimethoxyphenyl)-2-(3,3-diethoxypropyl)-2-ethylacetonitrile;

2-(3,4-dimethoxyphenyl)-2-(3,3-diethoxypropyl)-2-(but-2-yl)acetonitrile;and

2-(3,4-dimethoxyphenyl)-2-(3,3-diethoxypropyl)-2-(pent-3-yl)acetonitrile.

(C) Similarly, proceeding as in parts (A-B) above but substituting thecompounds prepared in Preparation 3(B) for the starting material, thefollowing compounds are prepared:

2-(1,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-methylacetonitrile;

2-(1,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-ethylacetonitrile;

2-(1,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-isopropylacetonitrile;

2-(1,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-(but-2-yl)acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-(pent-3-yl)acetonitrile;

2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-methylacetonitrile;

2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-ethylacetonitrile;

2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-isopropylacetonitrile;

2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-(but-2-yl)-acetonitrile;and

2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-(pent-3-yl)acetonitrile.

PREPARATION 5 (Intermediates of Formula 7)

(A) A solution of2-(3,4-dimethoxyphenyl)-2-(3,3-diethoxypropyl)-2-isopropylacetonitrile(97.6 g, 0.28 mol) in THF (1.4 L) and water (550 mL) was prepared at 55°C. Concentrated HCl (66 mL) was then added over 15 minutes, and themixture stirred for an additional 30 minutes. The THF was then removedin vacuo, and the aqueous remainder extracted with CH₂ Cl₂ (1.3 L) andwater (500 mL). The organic layer was separated, washed with saturatedaqueous NaHCO₃ (500 mL), and evaporated to yield2-(3,4-dimethoxyphenyl)-2-(3-oxopropyl)-2-isopropylacetonitrile (7, 71.7g, MS m/e 275 (M+)) as a thick oil.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 4(B) for2-(3,4-dimethoxyphenyl)-2-(3,3-diethoxypropyl)-2-isopropylacetonitrile,the following compounds are prepared:

2-(3-oxopropyl)-2-(3,4-dimethoxyphenyl)-2-methylacetonitrile;

2-(3-oxopropyl)-2-(3,4-dimethoxyphenyl)-2-ethylacetonitrile;

2-(3-oxopropyl)-2-(3,4-dimethoxyphenyl)-2-(but-2-yl)-acetonitrile;

2-(3-oxopropyl)-2-(3,4-dimethoxyphenyl)-2-(pent-3-yl)-acetonitrile;

2-(3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-methylacetonitrile;

2-(3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-ethylacetonitrile;

2-(3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-isopropylacetonitrile;

2-(3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-(but-2-yl)-acetonitrile;

2-(3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-(pent-3-yl)acetonitrile;

2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-methylacetonitrile;

2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-ethylacetonitrile;

2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-isopropylacetonitrile;

2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-(but-2-yl)-acetonitrile; and

2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-(pent-3-yl)acetonitrile.

PREPARATION 6 (Intermediates of Formula 8)

(A) A mixture of 2-(3,4-dimethoxyphenyl)-1-nitroethane (4, 135 g, 0.64mol), 2-(3,4-dimethoxyphenyl)-2-(3-oxopropyl)-2-isopropylacetonitrile(7, 156 g, 0.57 mol) and KF (19.3 g, anhydrous, Aldrich) in 2-propanol(2.0 L) was heated to 50°-55° C. for about 40 hours. The mixture wasthen cooled to room temperature and the isopropanol removed in vacuo.The residue was dissolved in CH₂ Cl₂ (1.6 L) and filtered through Celite(50 g). The filtrate was extracted with saturated aqueous NaHCO₃ (2×500mL), the organic layer evaporated, and the product recrystallized fromethyl acetate-hexane (1:1) to yield1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexan-3-ol(8, 205 g, m.p. 171°-173° C., MS m/e 486(M+)).

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 5(B) for2-(3,4-dimethoxyphenyl)-2-(3-oxopropyl)-2-isopropylacetonitrile (7), thefollowing compounds are prepared:

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol;and

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexan-3-ol.

(C) Similarly, proceeding as in parts (A-B) above but substituting thecompounds prepared in Preparation 2(B) for2-(3,4-dimethoxyphenyl)-1-nitroethane (4), the following compounds areprepared:

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol;and

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexan-3-ol.

PREPARATION 7 (Intermediates of Formula 9)

(A) A mixture of1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol(8, 75 g, 0.154 mol), 4-dimethylaminopyridine ("DMAP," 1.5 g, Aldrich),and acetic anhydride (23 mL) in CH₂ Cl₂ (700 mL) was heated at refluxfor 40 minutes to yield1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(9), which was used in the next step without isolation.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 6(B-C) for1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol,the following compounds are prepared:

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;and

1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane.

PREPARATION 8 (Intermediates of Formula 10)

(A) The reaction mixture containing1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(9) prepared in Preparation 7(A) was cooled to room temperature anddiluted with isopropanol (350 mL). Solid NaBH₄ (15 g, 0.4 mol) was addedover 15 minutes at 25° C. The mixture was then heated to reflux (about40° C.) for 15 hours, then cooled to 5° C. A solution of 10% HCl (30 mL)was slowly added, followed by water (100 mL). The organic layer wasextracted, washed with saturated aqueous NH₄ Cl (200 mL), and saturatedaqueous NaHCO₃ (200 mL). The organic layer was evaporated to yield1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(10, 58.7 g, m.p. 107°-110° C., MS m/e 470(M+)) as a pale yellow solid.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 7(B) for1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane,the following compounds are prepared:

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-B2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;and

1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane.

PREPARATION 9 (Intermediates of Formula 11)

(A) A mixture of1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(10, 58.7 g, 0.125 mol) and methanol (950 mL) was added to a flask, andevacuated to remove oxygen. The catalyst, 5% Pd in carbon (50% water, 19g, Engelhard Co.), was added under an N₂ atmosphere. After stirring for10 minutes at room temperature, solid HCO₂ NH₄ (65 g, Aldrich) wasadded, and the resulting mixture stirred for 1 hour. The mixture wasthen slowly heated to 50° C. for 48 hours, then cooled to roomtemperature and filtered through Celite (50 g). The solids were washedwith methanol (50 mL), the filtrates concentrated in vacuo, and theresulting solid dissolved in CH₂ Cl₂. The solution was extracted withsaturated aqueous NH₄ Cl (500 mL) and saturated aqueous NaHCO₃ (300 mL),and the organic layer evaporated to yield1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane (11, 52.3 g, MS m/e 440(M+))as a pale yellow oil.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 8(B) for1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane,the following compounds are prepared:

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane;and

1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyphenyl)hexane.

PREPARATION 10 (Intermediates of Formula 13)

(A) L-3,4-dimethoxyphenylalaninol (12) was prepared by the methoddescribed by A. W. Schrecker and J. L. Hartwell, J. Amer. Chem. Soc.,79, 3827 (1957). A solution of L-3,4-dimethoxyphenylalaninol (12, 23.3g, 110 mmol) in THF (400 mL) was mixed with di-t-butyldicarbonate (24.0g, 110 mmol) and the resulting solution heated at reflux for one hour.The mixture was then evaporated under reduced pressure and the residuefiltered through silica gel using ethyl acetate. The filtrate was thenevaporated to yieldL-3-(3,4-dimethoxyphenyl)-2-(t-butoxycarbonylamino)propan-1-ol (13, 32.4g, m.p. 92°-93° C., [α]_(D) ²⁵ =-19.6° (MeOH). Calculated for C₁₆ H₂₅NO₅ : C=61.72, H=8.09, N=4.50. Found: C=61.62, H=8.13, N=4.47.

(B) Similarly, proceeding as in part (A) above but substitutingD-3,4-dimethoxyphenylalaninol, L-3,4,5-trimethoxyphenylalaninol,D-3,4,5-trimethoxyphenylalaninol,L-3,4-dimethoxy-2,5-diethoxyphenylalaninol,D-3,4-dimethoxy-2,5-diethoxyphenylalaninol,L-3,4-dimethoxy-2,5-dipentoxyphenylalaninol, orD-3,4-dimethoxy-2,5-dipentoxyphenylalinol, forL-3,4-dimethoxyphenylalaninol, the following compounds are prepared:

D-3-(3,4-dimethoxyphenyl)-2-(t-butoxycarbonylamino)-propan-1-ol;

L-3-(3,4,5-trimethoxyphenyl)-2-(t-butoxycarbonylamino)propan-1-ol;

D-3-(3,4,5-trimethoxyphenyl)-2-(t-butoxycarbonylamino)propan-1-ol;

L-3-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-(t-butoxycarbonylamino)propan-1-ol;

D-3-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-(t-butoxycarbonylamino)propan-1-ol;

L-3-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-(t-butoxycarbonylamino)propan-1-ol;and

D-3-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-(t-butoxycarbonylamino)propan-1-ol.

PREPARATION 11 (Intermediates of Formula 14)

(A) A solution ofL-3-(3,4-dimethoxyphenyl)-2-(t-butoxycarbonylamino)propan-1-ol (13, 32.4g, 104 mmol), p-toluenesulfonyl chloride (29.8 g, 156 mmol), and DMAP(0.63 g) in pyridine (100 mL) was stirred at room temperature for twodays. The resulting mixture was then diluted with ether, washed withaqueous CuSO₄ and water, and the organic layer dried over MgSO₄ andevaporated. The residue was purified by medium pressure chromatography(30% ethyl acetate-hexane) to yieldL-3-(3,4-dimethoxyphenyl)-2-(t-butoxycarbonylamino)-1-tosyloxypropane(14, m.p. 146°-148° C., [α]_(D) ²⁵ =-15.4° (CHCl₃)). Calculated for C₂₃H₃₁ NO₇ S: C=59.34, H=6.71, N=3.01. Found: C=59.37, H=6.73, N=2.98.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 10(B) above forL-3-(3,4-dimethoxyphenyl)-2-(t-butoxycarbonylamino)propan-1-ol, thefollowing compounds are prepared:

D-3-(3,4-dimethoxyphenyl)-2-(t-butoxycarbonylamino)-1-tosyloxypropane;

L-3-(3,4,5-trimethoxyphenyl)-2-(t-butoxycarbonylamino)-1-toxyloxypropane;

D-3-(3,4,5-trimethoxyphenyl)-2-(t-butoxycarbonylamino)-1-toxyloxypropane;

L-3-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-(t-butoxycarbonylamino)-1-tosyloxypropane;

D-3-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-(t-butoxycarbonylamino)-1-toxyloxypropane;

L-3-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-(t-butoxycarbonylamino)-1-tosyloxypropane;and

D-3-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-(t-butoxycarbonylamino)-1-tosyloxypropane.

PREPARATION 12 (Intermediates of Formula 15)

(A) Vinylmagnesium bromide (37.3 mL of 1.6M THF solution) was added to a-5° C. suspension of CuI (5.8 g, 29.8 mmol) in THF (75 mL). The mixturewas cooled to -70° C. and a solution ofL-3-(3,4-dimethoxyphenyl)-2-(t-butoxycarbonylamino)-1-tosyloxypropane(14, 4.6 g, 9.9 mmol) in THF (80 mL) was added slowly. The mixture wasstirred at -70° C. for 30 minutes, then allowed to warm to 0° C. Theresulting mixture was poured into aqueous NH₄ Cl and extracted withether. The organic layer was dried over MgSO₄, evaporated, and theresidue purified by medium pressure chromatography to yieldL-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)pent-1-ene (15, 2.0g, m.p. 91°-92° C., [α]_(D) ²⁵ =-20.9° (MeOH). Calculated for C₁₈ H₂₇NO₄ : C=67.26, H=8.47, N=4.36. Found: C= 67.33, H=8.49, N=4.32.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 11(B) above forL-3-(3,4-dimethoxyphenyl)-2-(t-butoxycarbonylamino)-1-tosyloxypropane,the following compounds are prepared:

D-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)-pent-1-ene;

L-5-(3,4,5-trimethoxyphenyl)-4-(t-butoxycarbonylamino)pent-1-ene;

D-5-(3,4,5-trimethoxyphenyl)-4-(t-butoxycarbonylamino)pent-1-ene;

L-5-(3,4-dimethoxy-2,5-diethoxyphenyl)-4-(t-butoxycarbonylamino)pent-1-ene;

D-5-(3,4-dimethoxy-2,5-diethoxyphenyl)-4-(t-butoxycarbonylamino)pent-1-ene;

L-5-(3,4-dimethoxy-2,5-dipentoxyphenyl)-4-(t-butoxycarbonylamino)pent-1-ene;and

D-5-(3,4-dimethoxy-2,5-dipentoxyphenyl)-4-(t-butoxycarbonylamino)pent-1-ene.

PREPARATION 13 (Intermediates of Formula 16)

(A) A solution ofL-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)pent-1-ene (15, 1.6g, 5 mmol) in THF (10 mL) was added to a 0° C. solution ofdisiamylborane (7.5 mmol) in THF (25 mL). The mixture was stirred atroom temperature for one hour, cooled to 0° C., and 3N NaOH (1.7 mL) and30% H₂ O₂ (1.7 mL) added sequentially. The resulting solution wasstirred at room temperature for 30 minutes, diluted with ether, andwashed with water and brine. The ether was evaporated and the residuerecrystallized from ether/hexane to yieldD-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)pentan-1-ol (16, 1.2g, m.p. 73°-75° C., [α]_(D) ²⁵ =+0.89° (MeOH). Calculated for C₁₈ H₂₉NO₅ : C=63.69, H=8.61, N=4.13. Found: C=63.58, H=8.64, N=4.06.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 12(B) forL-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)-pent-1-ene, thefollowing compounds are prepared:

L-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)-pentan-1-ol;

L-5-(3,4,5-trimethoxyphenyl)-4-(t-butoxycarbonylamino)-pentan-1-ol;

D-5-(3,4,5-trimethoxyphenyl)-4-(t-butoxycarbonylamino)pentan-1-ol;

L-5-(3,4-dimethoxy-2,5-diethoxyphenyl)-4-(t-butoxycarbonylamino)pentan-1-ol;

D-5-(3,4-dimethoxy-2,5-diethoxyphenyl)-4-(t-butoxycarbonylamino)pentan-1-ol;

L-5-(3,4-dimethoxy-2,5-dipentoxyphenyl)-4-(t-butoxycarbonylamino)pentan-1-ol;and

D-5-(3,4-dimethoxy-2,5-dipentoxyphenyl)-4-(t-butoxycarbonylamino)pentan-1-ol.

PREPARATION 14 (Intermediates of Formula 17)

(A) A solution ofD-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)pentan-1-ol (16, 1.0g, 2.98 mmol) and triethylamine (1.3 mL) in CH₂ Cl₂ (15 mL) was cooledand methanesulfonyl chloride (0.26 mL, 3.3 mmol) was added. After 10minutes, the mixture was added to water and the organic layer separatedand dried over MgSO₄. The dichloromethane was evaporated and theresulting white solid was dissolved in acetone (10 mL). NaI (3 g) wasadded and the mixture was heated at reflux for 30 minutes. The mixturewas then poured in water, extracted with ether, and the ether washedwith aqueous NaHSO₃, water, and brine. The ether layer was then driedover MgSO₄ and evaporated to yield crudeD-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane (17)which was used at once.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 13(B) forD-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)-pentan-1-ol, thefollowing compounds are prepared:

L-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane;

L-5-(3,4,5-trimethoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane;

D-5-(3,4,5-trimethoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane;

L-5-(3,4-dimethoxy-2,5-diethoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane;

D-5-(3,4-dimethoxy-2,5-diethoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane;

L-5-(3,4-dimethoxy-2,5-dipentoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane;and

D-5-(3,4-dimethoxy-2,5-dipentoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane.

PREPARATION 15 (Intermediates of Formula 18)

(A) A solution of 2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrile (6a,1.3 g, 6 mmol), in THF (5 mL) was added to -70° C. solution of lithiumdiisopropylamide (LDA, 6 mmol) in THF (20 mL). After 10 minutes at -70°C., a solution of crudeL-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane (17,ca. 3 mmol) in THF (5 mL) was added and the resulting mixture allowed towarm to 0° C. Aqueous HCl was added and the mixture extracted withether. The organic layer was washed with water and brine, dried overMgSO₄, evaporated, and the residue purified by medium pressurechromatography (30% ethyl acetate-hexane) to yield(2R)-1-(3,4-dimethoxyphenyl)-2-t-butoxycarbonylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(18, 400 mg).

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 14(B) forD-5-(3,4-dimethoxyphenyl)-4-(t-butoxycarbonylamino)-1-iodopentane, thefollowing compounds are prepared:

(2S)-1-(3,4-dimethoxyphenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2R)-1-(3,4,5-trimethoxyphenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2S)-1-(3,4,5-trimethoxyphenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2R)-1-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2S)-1-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2R)-1-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;and

(2S)-1-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane.

PREPARATION 16 (Intermediates of Formula 19)

(A) A solution of(2R)-1-(3,4-dimethoxyphenyl)-2-t-butoxycarbonylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(18, 400 mg) in formic acid (5 mL) was heated at reflux for 15 minutes.The mixture was evaporated and the residue treated with formic-aceticanhydride (2 mL). Ether was added and the mixture washed with water,aqueous NaHCO₃, and brine, and the solution dried over Na₂ SO₄. Theether was evaporated and the residue purified by medium pressurechromatography using ethyl acetate. The first component to elute was(2R,6S)-1-(3,4-dimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(19A, 180 mg, [α]_(D) ²⁵ =-4.3° (MeOH)). The second component to elutewas (2R,6R)-1-(3,4-dimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(19B, 40 mg, [α]_(D) ²⁵ =+2.3° (MeOH)).

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 15(B) for(2R)-1-(3,4-dimethoxyphenyl)-2-t-butoxycarbonylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane,the following compounds are prepared:

(2S,6R)-1-(3,4-dimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2S,6S)-1-(3,4-dimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2R,6R)-1-(3,4,5-trimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2R, 6S)-1-(3,4,5-trimethoxyphenyl)-2-formylamino-B6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2S,6R)-1-(3,4,5-trimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2S,6S)-1-(3,4,5-trimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane;

(2R,6R)-1-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexane;

(2R,6S)-1-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexane;

(2S,6R)-1-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexane;

(2S,6S)-1-(3,4-dimethoxy-2,5-diethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexane;

(2R,6R)-1-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexane;

(2R,6S)-1-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexane;

(2S,6R)-1-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexane;and

(2S,6S)-1-(3,4-dimethoxy-2,5-dipentoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexane.

PREPARATION 17 (Intermediates of Formula 20)

(A) Phosphorous oxychloride (POCl₃, 2.3 mL) was added to a solution of(2R,6S)-1-(3,4-dimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexane(19A, 5.1 g, 11 mmol) in acetonitrile (75 mL) and the mixture stirred atroom temperature for two hours. The resulting mixture was evaporated,and the residue dissolved in ether and extracted with cold aqueous NH₄OH. The ether was evaporated, the residue was dissolved in ethanol (100mL), and sodium borohydride (0.5 g) added. The mixture was stirred forone hour, then added to water, acidified with HCl, and extracted withether. The organic layer was washed with brine, dried, and evaporated toa colorless oil to yield (3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(20A).

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 16(B) for (2R,6S)-1-(3,4-dimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane,the following compounds are prepared:

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-1,2,3,4-tetrahydroisoquinoline;and

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-1,2,3,4-tetrahydroisoquinoline.

PREPARATION 18 (Intermediates of Formula 21)

(A) A solution of 2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrile (6a)in toluene is slowly added to sodium amide (1.5 eq) in toluene, and theresulting mixture warmed to 80°-90° C. for one hour. The mixture wasthen cooled to 15° C. and 1-bromo-3-chloropropane (2 eq) slowly addedand stirred for two hours at room temperature. The mixture is thencarefully poured into ice water, extracted with CH₂ Cl₂, and vacuumdistilled to yield2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-chloropropyl)acetonitrile (21,b.p. 160°-165°/0.05 mmHg).

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 3(B-C) for2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrile, the following compoundsare prepared:

2-(3,4-dimethoxyphenyl)-2-methyl-2-(3-chloropropyl)-acetonitrile;

2-(3,4-dimethoxyphenyl)-2-ethyl-2-(3-chloropropyl)-acetonitrile;

2-(3,4-dimethoxyphenyl)-2-(but-2-yl)-2-(3-chloropropyl)acetonitrile;

2-(3,4-dimethoxyphenyl)-2-(pent-3-yl)-2-(3-chloropropyl)acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-methyl-2-(3-chloropropyl)-acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-ethyl-2-(3-chloropropyl)-acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-isopropyl-2-(3-chloropropyl)acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-(but-2-yl)-2-(3-chloropropyl)acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-(pent-3-yl)-2-(3-chloropropyl)acetonitrile;

2-(1,4-benzodioxan-2-yl)-2-methyl-2-(3-chloropropyl)-acetonitrile;

2-(1,4-benzodioxan-2-yl)-2-ethyl-2-(3-chloropropyl)-acetonitrile;

2-(1,4-benzodioxan-2-yl)-2-isopropyl-2-(3-chloropropyl)acetonitrile;

2-(1,4-benzodioxan-2-yl)-2-(but-2-yl)-2-(3-chloropropyl)acetonitrile;and

2-(1,4-benzodioxan-2-yl)-2-(pent-3-yl)-2-(3-chloropropyl)acetonitrile.

PREPARATION 19 (Intermediates of Formula 22)

(A) A solution of2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-chloropropyl)acetonitrile (22,21.4 g, 72 mmol), sodium iodide (30 g), and acetone (250 mL) was heatedat reflux for 12 hours. The mixture was then filtered, the acetoneevaporated, and the residue partitioned between ether and water. Theorganic layer was washed with aqueous NaSO₃ and brine, dried over Na₂SO₄, and evaporated to yield2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22, 28g) as a thick oil.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 18(B) for2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-chloropropyl)acetonitrile, thefollowing compounds are prepared:

2-(3,4-dimethoxyphenyl)-2-methyl-2-(3-iodopropyl)-acetonitrile;

2-(3,4-dimethoxyphenyl)-2-ethyl-2-(3-iodopropyl)-acetonitrile;

2-(3,4-dimethoxyphenyl)-2-(but-2-yl)-2-(3-iodopropyl)acetonitrile;

2-(3,4-dimethoxyphenyl)-2-(pent-3-yl)-2-(3-iodopropyl)acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-methyl-2-(3-iodopropyl)-acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-ethyl-2-(3-iodopropyl)-acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-isopropyl-2-(3-iodopropyl)acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-(but-2-yl)-2-(3-iodopropyl)acetonitrile;

2-(1,3-benzodioxol-2-yl)-2-(pent-3-yl)-2-(3-iodopropyl)acetonitrile;

2-(1,4-benzodioxan-2-yl)-2-methyl-2-(3-iodopropyl)-acetonitrile;

2-(1,4-benzodioxan-2-yl)-2-ethyl-2-(3-iodopropyl)-acetonitrile;

2-(1,4-benzodioxan-2-yl)-2-isopropyl-2-(3-iodopropyl)-acetonitrile;

2-(1,4-benzodioxan-2-yl)-2-(but-2-yl)-2-(3-iodopropyl)acetonitrile; and

2-(1,4-benzodioxan-2-yl)-2-(pent-3-yl)-2-(3-iodopropyl)acetonitrile.

PREPARATION 20 (Intermediates of Formula 23)

(A) A 1.6M solution of n-butyllithium in hexane (91.8 mL, 147 mmol) wasadded to a -20° C. solution of diisopropylamine (21 mL, 150 mmol) in THF(480 mL). Hexamethylphosphoramide (56 mL) was added and the mixturemaintained at -20° C. while a solution of3-(3,4-dimethoxyphenyl)propionic acid (15.1 g, 72 mmol) in THF (75 mL)was added. The resulting solution was stirred at room temperature forone hour, and then cooled to -50° C. A solution of2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22,27.9 g, 72 mmol) was added, and the mixture allowed to warm to roomtemperature while stirring for 12 hours. The resulting mixture was addedto water, acidified with HCl, and extracted three times with ether. Theorganic layer was washed with aqueous Na₂ SO₃ and brine, dried over Na₂SO₄, and evaporated to yield1-(3,4-dimethoxyphenyl)-2-carboxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(23, 31 g) as a thick oil.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 19(B) for2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile, thefollowing compounds are prepared:

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(3,4-dimethoxyphenyl)-6-methyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(3,4-dimethoxyphenyl)-6-ethyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(3,4-dimethoxyphenyl)-6-(but-2-yl)-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(3,4-dimethoxyphenyl)-6-(pent-3-yl)-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,3-benzodioxol-2-yl)-6-methyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,3-benzodioxol-2-yl)-6-ethyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,3-benzodioxol-2-yl)-6-isopropyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,3-benzodioxol-2-yl)-6-(but-2-yl)-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,3-benzodioxol-2-yl)-6-(pent-3-yl)-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-methyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-ethyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-isopropyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-(but-2-yl)-6-cyanohexane;and

1-(3,4-dimethoxyphenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-(pent-3-yl)-6-cyanohexane.

PREPARATION 21 (Intermediates of Formula 19 via Scheme III)

(A) A mixture of1-(3,4-dimethoxyphenyl)-2-carboxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(24, 16.6 g, 35 mmol), triethylamine (5.9 mL), diphenylphosphoryl azide(7.6 mL, 35 mmol), and toluene (200 mL) was heated to reflux temperatureand maintained at reflux for 15 minutes. The solvents were removed underreduced pressure and the residue dissolved in dimethoxyethane (DME, 200mL). The solution was cooled in an ice bath and NaBH₄ (1.6 g) slowlyadded. The solution was stirred for one hour, concentrated en vacuo, andpartitioned between aqueous HCl (5%) and ethyl acetate. The organiclayer was washed with water and brine, dried over Na₂ SO₄, andevaporated to yield1-(3,4-dimethoxyphenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(19, 20.6 g) as a diastereomeric mixture of thick oils.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 20(B) for1-(3,4-dimethoxyphenyl)-2-carboxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane,the following compounds are prepared:

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(3,4-dimethoxyphenyl)-6-methyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(3,4-dimethoxyphenyl)-6-ethyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(3,4-dimethoxyphenyl)-6-(but-2-yl)-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(3,4-dimethoxyphenyl)-6-(pent-3-yl)-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,3-benzodioxol-2-yl)-6-methyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,3-benzodioxol-2-yl)-6-ethyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,3-benzodioxol-2-yl)-6-isopropyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,3-benzodioxol-2-yl)-6-(but-2-yl)-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,3-benzodioxol-2-yl)-6-(pent-3-yl)-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,4-benzodioxan-2-yl)-6-methyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,4-benzodioxan-2-yl)-6-ethyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,4-benzodioxan-2-yl)-6-isopropyl-6-cyanohexane;

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,4-benzodioxan-2-yl)-6-(but-2-yl)-6-cyanohexane;and

1-(3,4-dimethoxyphenyl)-2-formylamino-6-(1,4-benzodioxan-2-yl)-6-(pent-3-yl)-6-cyanohexane.

EXAMPLE 1 (Compounds of Formula 1 via Scheme I)

(A) A mixture of1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane(11, 52.3 g, 0.12 mol), paraformaldehyde (27 g, Aldrich) and formic acid(97%, 380 mL) was heated at 85°-95° C. for 4-5 hours. Most of the formicacid was removed by vacuum distillation, and the residue cooled to roomtemperature and diluted with ethyl acetate (700 mL) and water (300 mL).Saturated brine (300 mL) was carefully added, and the resulting mixtureextracted with brine (300 mL). The organic layer was then separated andconcentrated to about 100 mL. The resulting mixture was applied to asilica gel column (300 g silica gel) and eluted with ethyl acetate.After 500 mL of eluate was collected, the remainder was eluted withacetone. The product fractions were collected and evaporated to yieldracemic3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline(1, 53.7 g, MS m/e 466(M+)) as a thick oil.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 9(B) for1-(3,4-dimethoxyphenyl)-2-amino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane,the following compounds are prepared:

3-[4-(3,4-dimethoxyphenyl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(but-2-yl)-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(pent-3-yl)-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-methyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-ethyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(but-2-yl)-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(pent-3-yl)-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-methyl-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-ethyl-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(but-2-yl)-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(pent-3-yl)-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-methyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-ethyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(but-2-yl)-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(pent-3-yl)-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(but-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(pent-3-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(but-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(3,4-dimethoxyphenyl)-4-(pent-3-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;

3-[4-(1,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline;and

3-[4-(1,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline.

EXAMPLE 2 (Compounds of Formula 1 via Scheme 2)

(A) A mixture of (3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(20A, ca. 5 g), formalin (20 mL) and formic acid (25 mL) was stirred forone hour at 100° C., cooled to room temperature, and added to water. Theresulting mixture was basified with NH₄ OH and extracted three timeswith ether. The organic extract was washed with brine, dried over MgSO₄,and evaporated to yield crude (3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline((-)-1A).

The crude free base was dissolved in ethanol, acidified with HCl, andether added until crystallization began to yield (3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl((-)-1A·HCl, m.p. 110°-113° C., [α]_(D) ²⁵ =-24.4° (MeOH)). Calculatedfor C₂₈ H₃₉ ClN₂ O₄ ·0.5H₂ O: C=65.74, H=7.78, N=5.48. Found: C=65.69,H=7.89, N=5.46.

(B) Similarly, proceeding as in part (A) above but substituting thecompounds prepared in Preparation 17(B) for (3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline,the following compounds are prepared:

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl;and

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl.

EXAMPLE 3 (Compounds of Formula 1 via Scheme 2)

(A) A mixture of (3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(20A, ca. 5 g), LDA (1 eq) and propyltosylate (1.5 eq) in THF (200 mL)was stirred for one hour at 70° C., cooled to room temperature, andadded to water. The resulting mixture was acidified with HCl andextracted three times with ether. The organic extract was washed withaqueous NaHCO₃ and brine, dried over MgSO₄, and evaporated to yieldcrude (3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-propyl-1,2,3,4-tetrahydroisoquinoline((-)-1A).

(B) Similarly, proceeding as in part (A) above but substitutingethyltosylate, isopropyltosylate, butyltosylate, or 2-pentyltosylate,the following compounds are prepared:

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-(2-propyl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-butyl-1,2,3,4-tetrahydroisoquinoline;and

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-pent-2-yl-1,2,3,4-tetrahydroisoquinoline.

(C) Similarly, proceeding as in parts (A-B) above but substituting thecompounds prepared in Preparation 17(B) for (3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline,the following N-alkyl compounds are prepared:

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-ethyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl-6,7-dimethoxy-5,8-dipentoxyphenyl-N-butyl-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3R,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;

(3S,4'R)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline;and

(3S,4'S)-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyphenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisoquinoline.

EXAMPLE 4 (Salts of Compounds of Formula 1)

(A) The free base,3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline(1, 15 g, 0.032 mol) was dissolved in isopropanol (70 mL) at 70° C., and6M HCl in isopropanol (5.6 mL) slowly added. After cooling to roomtemperature, ether (40 mL) was added until the solution became cloudy(saturated), and the resulting mixture stirred overnight. The resultingsolid was collected, washed thoroughly with ether-isopropanol (1:1, 50mL), and dried in vacuo at 50° C. to yield3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline·HCl(1·HCl, 13.7 g, m.p. 115°-120° C.) as a white powder.

(B) Similarly, proceeding as in part (A) above, but substituting thecompounds prepared in Example 1(B), the corresponding hydrochloridesalts are prepared.

(C) Similarly, proceeding as in parts (A-B) above, but substitutinghydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, aceticacid, propionic acid, glycolic acid, pyruvic acid, malonic acid,succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, or p-toluenesulfonic acid for hydrochloricacid, the corresponding salts are prepared.

EXAMPLE 5 (Formulations)

The following example illustrates the preparation of representativepharmaceutical formulations containing an active compound of formula 1,e.g.,3-[4-(3,4-dimethoxyphenyl)-4-cyano-4-isopropylbutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline(1).

    ______________________________________                                        I.V. Formulation                                                              ______________________________________                                        Active compound        0.01   g                                               Propylene glycol       20.0   g                                               Polyethylene glycol 400                                                                              20.0   g                                               Tween 80               1.0    g                                               0.9% Saline solution qs                                                                              100.0  mL                                              ______________________________________                                    

The active compound is dissolved in propylene glycol, polyethyleneglycol 400 and Tween 80. A sufficient quantity of 0.9% saline solutionis then added with stirring to provide 100 mL of the I.V. solution whichis filtered through a 0.2 micron membrane filter and packaged understerile conditions.

    ______________________________________                                        TABLET FORMULATION parts by weight                                            ______________________________________                                        Active compound    25.0                                                       Magnesium stearate  0.2                                                       Pregelatinized starch                                                                            74.8                                                       ______________________________________                                    

The above ingredients are dry-blended and loaded into #0 capsulescontaining about 100 mg active compound per capsule.

EXAMPLE 6 (Spontaneously Hypertensive Rat Assay)

Twenty-four previously trained adult male spontaneously hypertensiverats are distributed into 6 groups (4 animals per group) withapproximately equal mean systolic blood pressures. The 6 groups are thenstudied concurrently in a 2-day compound screening procedure.

Test compounds are randomly assigned to each group. Five groups receivepotential antihypertensive agents and 1 control group receives vehicleonly (water and Tween).

At approximately 17 hours prior to the first day of dosing food isremoved from the rat cages. On the morning of Day 1, a group of 4 ratsis orally dosed (by gavage) with 12.5 mg/kg or 25 mg/kg of a compound offormula 1 dissolved/suspended in water (using 2-3 drops Tween 80) with ahomogenizer at concentrations such that 0.1 mL of solution isadministered per 10 g of body weight. At 41/2 hours post dose, food isput back in the cages and the rats are allowed to eat for 21/2 hours,after which food is again removed. On the morning of Day 2, rats areorally dosed as described above. Immediately after dosing, the rats areput in restrainers and placed in a heated chamber (30±1.0° C.) for fourhours. Normal feeding resumes at the end of the study on Day 2.

Systolic blood pressure (i.e., pressure at the appearance of the firstpulse) is recorded using photoelectric transducers. The coccygealarteries of 3 rats (in a horizontal group) are simultaneously occludedby pump-inflated tail cuffs that are automatically inflated to 300 mmHgand then deflated. A pressure curve and tail pulses are simultaneouslymonitored on an MFE recorder. Four consecutive (at 30 second intervals)traces are recorded for each rat in a given horizontal group at one,two, three and four hours post compound administration. Subsequenthorizontal groups are automatically tested in the same manner.

The mean systolic blood pressure (SBP) of each rat at each observationtime is calculated. The SBP of the animals in each dose group iscompared to the SBP of the animals in the control group (vehicle only)at each observation time using a one-way analysis of variance test. Dataexhibiting p≦0.05 at any observation time is considered to indicate acompound exhibiting significant antihypertensive activity. Compoundssignificantly decreasing blood pressure 20 mmHg or more from controlvalues at all four observation times are considered worthy of furtherexamination. In these instances heart rates were calculated and testedfor significant change from control heart rate values using thetwo-tailed test. Pressures are read at hours 1, 2, 3 and 4 after dosingon both days 1 and 2. The compounds of the invention exhibit positiveantihypertensive activity in this test.

EXAMPLE 7 (Canine Echocardiography Assay)

A group of mongrel dogs, 18 to 25 kg, is chosen for the clarity ofimages that can be obtained from them via ultrasonic two-dimensionalechocardiography (2DE). Animals from this group are used in twodifferent models employing 2DE. In the first model the dogs areanesthetized; in the second they are conscious and non-sedatedthroughout the test drug administration.

In both models a small branch of femoral artery is cannulated, via anarterial cutdown, with a length of water-filled tubing connected to apressure transducer. In the conscious model, the femoral cutdown site isanesthetized with a local subcutaneous injection of 2% Lidocaine. Thistransducer provides a means to monitor blood pressure. Blood pressureand ECG are recorded on a two channel chart recorder.

An ultrasound realtime scanner, connected to a 3 MgHz endfiretransducer, placed in a right parasternal approach on the fourth offifth intercostal space, produces the 2DE images. Images include a longaxis view of the left ventricle defined as simultaneously imaging theapex, mitral valve, and a round left atrium. Additionally, short axisviews at the high papillary muscle level are obtained. All images arerecorded on video tape for later analysis. Analysis is accomplishedusing a computerized graphics program interfaced with the videorecorderand a bit pad.

In the first model the dogs are anesthetized with sodium pentobarbital.They are placed on their right sides on a support that allows access,via a cutout to the right parasternal area. Doses of 50, 100, 200, and500 μg/kg of a compound of the invention are administered intravenouslyover the course of the experiment day. The compound is dissolved in 2:1distilled water-dimethyl acetamide. Control values are obtained for eachdose and further measurements are taken at 3, 5, 10, 15, and 30 minutesafter administration of each dose.

In the second model the dogs are trained to stand quietly for severalhours in a sling. The right parasternal area is accessed via abuttoned-down panel in the sling. Doses of 5.0 and 5.5 mg/kg of acompound of the invention are administered intravenously, dissolved in7:1 distilled water-ethanol, as are doses of 1.5 and 1.0 mg/kg of acompound of the invention dissolved in 3:1 distilled water-dimethylacetamide. Additionally, doses of 5, 2, 1, and 0.75 mg/kg of a compoundof the invention are administered orally, with the compound in a gelatincapsule. Control values are obtained prior to each dose. During theintravenous studies additional measurements are obtained at intervals of5, 10, 15, 30, 45, and 60 minutes after the administration of each dose.During the oral studies additional measurements are obtained atintervals of 10, 20, 30, 45, 60, 75, 90. 105, 120, and 180 minutes afterthe administration of each dose. The compounds of the inventiondemonstrate positive activity in this assay.

EXAMPLE 8 (Anesthetized Dog Assay)

Mongrel dogs ranging in weight from 14 to 21 kg are anesthetized withpentobarbital sodium (35 mg/kg, i.v.), intubated and the chest opened atthe left fifth intercostal space. The animals are instrumented tomeasure the following parameters: systolic, diastolic and mean bloodpressure, heart rate, left ventricular pressure, left ventricular dp/dtmax, pulmonary capillary wedge pressure, central venous pressure,cardiac output, systemic vascular resistance, contractile force, andcoronary blood flow.

Left ventricular pressure is measured using a Millar micro-tip catheter.Electronic differentiation of this signal provides dp/dt maximum.Systolic, diastolic and mean blood pressure, and central venous pressureare evaluated using fluid-filled Statham pressure transducers. Cardiacoutput and pulmonary capillary wedge pressure are measured using aSwan-Ganz catheter connected to a Statham water-filled pressuretransducer and a Gould Cardiac Index Computer. Contractile force isdetermined via a Walton-Brodie Strain gauge arch sewn to the leftventricle. Systemic vascular resistance is calculated using cardiacoutput and blood pressure measurements. Epicardial coronary blood flowis measured with an electromagnetic flow probe (Carolina MedicalElectronics, Co.). Myocardial blood flow is evaluated usingradioactive-labelled microspheres (5: ⁸⁵ Sr, ¹⁴¹ Ce, ⁵¹ Cr, ¹¹³ Sn, ⁴⁶Sc). This data is counted with a Packard model 3500 gamma counter and aCanberra Model Multichannel Analyzer, and analyzed with the aid ofSyntex-developed software run on a HP1000 Computer.

A compound of the invention is prepared for administration in a vehicleof dimethylacetamide and saline (for intravenous use) ordimethylacetamide and water (for intraduodenal use). Appropriatecontrols are also examined.

One group of animals is given a compound of the invention intravenouslyat the following doses: 25, 50, 100, 200 and 500 μg/kg. The above-namedparameters are monitored for at least 30 minutes after each dose.

The second group of animals is given a compound of the inventionintraduodenally at a dose of 5 mg/kg. The above mentioned parameters aremonitored for 3 to 4 hours after drug administration.

In a third group of animals, a compound of the invention is administeredintracoronary to determine the direct local effects of the compound. Allof the above-mentioned parameters are monitored for 10-15 minutes afterdrug administration except myocardial blood flow (microsphere method).The doses administered are 1, 2, 5, 10, and 20 mg/kg.

In a fourth group of animals, a compound of the invention isadministered intravenously after pretreatment with d-, l-, ordl-propranolol (0.5 mg/kg, i.v.). All parameters are monitored for onehour after drug administration.

The data is summarized with mean values ± the standard error from themean. When indicated, statistics are done with paired or unpairedStudent's t-test. The compounds of the invention exhibit positiveactivity in this assay.

EXAMPLE 9 (Rat Aortic Strip Assay)

Four male Sprague-Dawley rats (250-300 g per rat, obtained from Bantin &Kingman) were sacrificed by cervical dislocation. The thoracic aortaswere quickly removed and the adventitial connective tissue carefullyremoved. The aortas were cut into helical strips 2-3 cm wide and 3 cmlong. The strips were mounted vertically in tissue baths containing 10mL modified Krebs solution at 37° C., and allowed to equilibrate with agas mixture of 95% O₂ and 5% CO₂.

An initial tension of 1 g was applied to the strips. The systems wereallowed to equilibrate for one hour, during which period the strips werewashed six times. The strips were then contracted with either BaCl₂(10⁻³ M) or phenylephrine (10⁻⁷ M), and were allowed to reach a steadyresponse. The strips were then subjected to stepwise increasingconcentrations of compounds of the invention and the responses recordedusing Statham UC-2 transducers and a Beckman R611 Dynograph recorder.The compounds of the invention demonstrated high activity as calciumchannel blockers in this assay.

EXAMPLE 10 (Calcium Blockade Tissue Selectivity)

Four male New Zealand White rabbits (2.5-3.5 Kg per rabbit, Elkhorn)were sacrificed using pentobarbital sodium (50 mg/Kg, i.v. via the earvein) and quickly decapitated. The brains were quickly removed andplaced in a dish of modified Krebs buffer aerated with 95% O₂ /5% CO₂.The basilar arteries were dissected out and placed in a separate aerateddish of buffer. A section of central ear artery (30 mm) from each rabbitwas removed from the middle of the ear and placed in an aerated bufferdish. The basilar and ear arteries were carefully cleaned and cut intocross-sectional rings. Basilar artery rings were about 3 mm long; earartery rings were about 2 mm long. The rings were mounted in holders intissue baths containing 10 mL modified Krebs solution at 37° C., andallowed to equilibrate with a gas mixture of 95% O₂ and 5% CO₂.

An initial tension of 0.5 g was applied to the rings. The systems wereallowed to equilibrate for one hour, during which period the rings werewashed six times. The rings were then contracted with KCl sufficient toevoke a 1 g contraction, and were allowed to reach a steady response.The rings were then subjected to stepwise increasing concentrations ofcompounds of the invention and the responses recorded using Statham UC-2transducers and a Beckman R611 Dynograph recorder. The compounds of theinvention demonstrated high activity and good selectivity as calciumchannel blockers in this assay.

What is claimed is:
 1. A compound of the formula ##STR11## or apharmaceutically acceptable acid addition salt thereof, wherein R₁ andR₂ are each independently --H or lower alkoxy;R₃ and R₄ are eachindependently lower alkyl; and R₅ and R₆ are each --OCH₃, or togetherform --OCH₂ O-- or --OCH₂ CH₂ O--.
 2. The compound of claim 1 wherein R₄is isopropyl.
 3. The compound of claim 2 wherein R₃ is methyl.
 4. Thecompound of claim 3 wherein R₁ and R₂ are each --H.
 5. The compound ofclaim 4 wherein R₅ and R₆ are each --OCH₃.
 6. The compound of claim 5which is3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline.7. The compound of claim 5 wherein the stereochemistry at C₃ is S. 8.The compound of claim 7 which is (3S,4'S)3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline.9. A pharmaceutical composition for treating angina, hypertension orcongestive heart failure, comprisinga pharmaceutically acceptablecarrier; and an effective amount of a compound of formula 1, ##STR12##wherein R₁ and R₂ are each independently --H or lower alkoxy; R₃ and R₄are each independently lower alkyl; and R₅ and R₆ are each --OCH₃, ortogether form --OCH₂ O-- or --OCH₂ CH₂ O--.
 10. The composition of claim9 wherein said compound of formula 1 is (racemic)3-[4-(3,4-dimethoxyphenyl)-4-cyano-4-isopropylbutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline.